“We found that TCGA efforts had contributed to a better understanding of the clinical settings in which TRK fusions occur. Also, TCGA data helped confirm that TRK fusions were typically present in the absence of other known oncogenic drivers,” said Dr. Bilenker. “Taken together, these insights helped point the way to clinical settings we might not have considered, while increasing our confidence that TRK fusions were likely to be oncogenic drivers susceptible to therapeutic intervention.”

Hitting the Target

So far in its clinical testing, LOXO-101 treatment has led to tumor regressions in TRK fusion-positive tumors in six different cancer types: thyroid cancer, lung cancer, salivary cancer, GI stromal cancer, sarcoma, and infantile fibrosarcoma.

“We think it’s pretty exciting,” said Dr. Bilenker. “[TRK fusions] may be one of the first molecular targets that is free of rigid anatomic classifications. Our regulatory conversations now center around defining this patient population by genetic event rather than by anatomic diagnosis.”

TRK gene fusions are alterations to DNA in which a gene for a kinase enzyme, either NTRK1, NTRK2, or NTRK3, moves from its original position on a chromosome to another position where it is more highly expressed and constitutively active, causing cells with these lesions to grow into cancer. Loxo Oncology collaborated with Array Biopharma to develop LOXO-101, a specific inhibitor to TRK fusions that blocks the function of the kinase.

When One Bullseye is Not Enough

Though TRK-fusion inhibitors are new therapies, Loxo Oncology knows that patients who originally respond to a targeted therapy often begin to progress because their cancer develops resistance. If this happens with patients receiving LOXO-101, Loxo Oncology wants to be ready. They supported academic collaborations to identify potential resistance mechanisms that would make LOXO-101 less effective, while collaborating with Array Biopharma to design second generation inhibitors capable of re-inducing drug sensitivity in the setting of these so-called acquired resistance mutations.

“We are seeing that a region of the kinase becomes mutated such that the kinase inhibitor has trouble binding with the same potency. We developed a drug [with Array Biopharma called LOXO-195] that’s shaped differently to avoid that new amino acid to induce sensitivity,” explained Dr. Bilenker.

Other Opportunities from TCGA data

Dr. Bilenker’s team has found other leads in the TCGA data. In particular, they have focused on RET gene fusions that have been identified in several cancer types studied by TCGA, including lung, papillary thyroid, medullary thyroid, and colon cancers. Currently, patients with RET fusions are sometimes treated with investigational promiscuous inhibitors that target several different kinds of kinases, with promising early results. However, there has never been a selective RET inhibitor, and thus, the full potential of this target has yet to be explored.

“Like TRK fusions, we believe RET fusions are oncogenic drivers, so we’re optimistic that a single-agent drug like our RET inhibitor will be able to show the kinds of responses we’ve been fortunate to see with LOXO-101,” said Dr. Bilenker.

Bringing Genomics to the Clinic

FDA’s breakthrough designation for LOXO-101 indicates that Loxo Oncology’s approach to treating patients based on the genomic changes that define their cancer shows great promise. But in order to get these drugs to the right patients, Dr. Bilenker emphasized that clinical oncologists need to embrace comprehensive genomic testing for all patients.

“We need the clinical community to adopt the kind of genetic characterization that TCGA does for the research field,” explained Bilenker. “The more comprehensive and universal access is, the more patients can be identified for appropriate therapies.”